ProjectSummary Viruses exploit cell surface receptors to gain access to the interior of host cells. These receptors are now appreciatedasmajorobstaclestovirusspillover,aprocessbywhichanimalvirusesmovefromonehostspecies intoanother.Inthemanydocumentedexamplesofspillover,virusestypicallyusethesameentryreceptorinthe old and new host, but need to acquire mutations to make them compatible with the specific ortholog of that receptor found in the new host. Diverse viruses such as avian influenza viruses, rodent arenaviruses, MERS coronavirus,andpossiblySARSandEbolavirusesallovercamereceptorbarriersinhumansastheytransmitted from their animal hosts. Here, we explore the following hypothesis of disease emergence: viruses can more easily overcome receptor barriers when host individuals of specific receptor genotypes come into contact.Weusethesimianimmunodeficiencyvirus(SIV)reservoirinAfricanprimatesasamodelforthis,and investigatetherolethattheSIV/HIVreceptors,CD4andCCR5,playinlimitingspilloveroftheseviruses.Primate lentiviruses(SIV/HIV)areanexcellentmodelbecausetheHIV/SIVreceptorsCD4andCCR5serveassignificant hostbarrierstothespilloverofthesevirusesbetweenprimatespecies.Weandothershaveshownthat(1)CD4 andCCR5varyfromonespeciestothenextintheirabilitytoserveasreceptorsforHIV/SIV,and(2)different individuals within primate populations have different virus susceptibilities because of receptor polymorphisms. Weleveragegeneticdataandbiomaterialsfromapproximately1,300primatesrepresenting15differentspecies, and a broad array of different HIV and SIV variants, to test the idea that certain individuals within populations arebetterpoisedtotransmitorreceiveinfectionduringspilloverscenarios.Themaininnovationoftheproposal is to define the role of host genetic variation in disease emergence, beyond a strict focus on the evolutionary properties of viruses. The project will aid in our understanding of the evolutionary processes leading to the emergenceofnewdiseases.Itissignificantbecausetheworkherewillbewidelyapplicabletodiverseviruses beyondlentiviruses,andtohostbarriersbeyondreceptorblocks.